It is known that physiologically active polypeptides or their derivatives exhibit a variety of pharmacological activities in vivo. Some of these have been produced on a large scale by utilizing Escherichia coli, yeasts, animal cells or host animals such as goat and hamsters using recently developed genetic engineering and cell technology, and put to medicinal use. However, these physiologically active polypeptides must be frequently administered because of the generally short biological half-life. The repeated injections takes a significant physical burden on patients.
For instance, growth hormone (hereafter sometimes referred to as GH), a representative hormone which is originally produced and secreted in the anterior portion of the pituitary gland, is a physiologically active polypeptide having widely diverse physiological activities such as promotion of growth in the body, metabolism of glucose and lipids, anabolism of protein, and cell proliferation and differentiation. And GH is produced on a large scale by utilizing Escherichia coli using genetic recombination technology, and put to medicinal use clinically and worldwidely. However, GH must be frequently administered in order to maintain an effective blood concentration because of the short biological half-life. Especially, in the case of pituitary dwarfism, a daily subcutaneous administration to infants or young patients over a long period of time ranging from a few months to at least 10 years is conducted practically.
To overcome this problem, various attempts have been made to develop a sustained-release preparation comprising a physiologically active polypeptide.
JP-A 3055/1996 (EP-A 633020) discloses a method of producing a sustained-release preparation which comprises permitting a water-soluble polypeptide to permeate into a biodegradable matrix comprising a biodegradable polymer and a metal salt of a fatty acid in an aqueous solution, and a sustained-release microcapsules (hereafter sometimes referred to as MC) prepared by this method.
JP-A 217691/1996 (WO 96/07399) discloses production of a water-insoluble or slightly water-soluble polyvalent metal salt by using a water-soluble peptide type of physiologically active substance and an aqueous solution of zinc chloride etc., and a method of producing a sustained-release preparation containing this salt and a biodegradable polymer.
WO 94/12158 discloses addition of a polymer erosion rate modulating agent such as zinc hydroxide in an amount of 0.1 to 30% (w/w) relative to the polymer to a polymer solution, as a method of producing a sustained-release preparation comprising human GH and biodegradable polymer. This publication further discloses a method of producing MC as porous particles by spraying a solution of human GH and a polymer in an organic solvent into liquid nitrogen with biological activity retained.
WO 92/17200 and Nature Medicine, Vol. 2, p. 795 (1996) disclose a method of producing a sustained-release preparation by using a zinc salt of human GH.
WO 95/29664 discloses a method of producing MC which comprises the steps of dispersing a metal salt such as zinc carbonate in a solid state in a polymer solution, adding a physiologically active substance such as hormones, and dispersing the physiologically active substance and a metal cation component separately through a biodegradable polymer.
Although, as described above, various attempts have been made to produce a sustained-release preparation with a physiological activity of a physiologically active polypeptide retained, a clinically satisfying preparation has not been obtained yet since some physiologically active polypeptides have problems such as a low entrapment ratio of the physiologically active polypeptide in the preparation, an excess release at an initial stage after administration, an unattained constant release over a long period of time, and an unretained satisfying blood concentration over a long period of time. Further, production methods, in many cases, are not suitable for industrialization which premises a large-scale production in the present situation.